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Definitions

• the present invention relates generally to the field of ligands for nicotinic acetylcholine receptors (nAChR), activation of nAChRs, and the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors, especially of the brain. Further, this invention relates to novel compounds, which act as ligands for the ⁇ 7 nAChR subtype, methods of preparing such compounds, compositions comprising such compounds, and methods of use thereof.
• nAChR nicotinic acetylcholine receptors
• muscarinic receptors There are two types of receptors for the neurotransmitter, acetylcholine: muscarinic receptors and nicotinic receptors, based on the selectivity of action of muscarine and nicotine, respectively.
• Muscarinic receptors are G-protein coupled receptors.
• Nicotinic receptors are members of the ligand-gated ion channel family. When activated, the conductance of ions across the nicotinic ion channels increases.
• Nicotinic alpha-7 receptor protein forms a homo-pentameric channel in vitro that is highly permeable to a variety of cations (e.g., Ca ++ ).
• Each nicotinic alpha-7 receptor has four transmembrane domains, named M1, M2, M3, and M4.
• the M2 domain has been suggested to form the wall lining the channel. Sequence alignment shows that nicotinic alpha-7 is highly conserved during evolution.
• the M2 domain that lines the channel is identical in protein sequence from chicken to human.
• the nicotinic alpha-7 receptor channel is expressed in various brain regions and is believed to be involved in many important biological processes in the central nervous system (CNS), including learning and memory. Nicotinic alpha-7 receptors are localized on both presynaptic and postsynaptic terminals and have been suggested to be involved in modulating synaptic transmission. It is therefore of interest to develop novel compounds, which act as ligands for the ⁇ 7nACh receptor subtype, for the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors.
• This invention relates to novel compounds, which act as ligands for the ⁇ 7 nACh receptor subtype, methods of preparing such compounds, compositions comprising such compounds, and methods of use thereof.
• the present invention includes compounds of Formulas I, II, III, or IV: wherein
• A when A is an indazolyl group of subformula (a), it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3-position.
• A when A is a benzothiazolyl group of subformula (b), it is preferably attached to the remainder of the compound via its 4 or 7 position.
• A When A is a benzoisothiazolyl group of subformula (c), it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3-position.
• A is a benzisoxazolyl group of subformula (d), it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3-position.
• A when A is an indazolyl group of subformula (a), it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3-position.
• A when A is a benzothiazolyl group of subformula (b), it is preferably attached to the remainder of the compound via its 4 or 7 position.
• A When A is a benzoisothiazolyl group of subformula (c), it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3-position.
• A is a benzisoxazolyl group of subformula (d), it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3-position.
• A when A is an indazolyl group of subformula (a), it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3-position.
• A when A is a benzothiazolyl group of subformula (b), it is preferably attached to the remainder of the compound via its 4 or 7 position.
• A When A is a benzoisothiazolyl group of subformula (c), it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3-position.
• A is a benzisoxazolyl group of subformula (d), it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3-position.
• A when A is an indazolyl group of subformula (a), it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3-position.
• A when A is a benzothiazolyl group of subformula (b), it is preferably attached to the remainder of the compound via its 4 or 7 position.
• A When A is a benzoisothiazolyl group of subformula (c), it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3-position.
• A is a benzisoxazolyl group of subformula (d), it is preferably attached to the remainder of the compound via its 3, 4 or 7 position, particularly via the 3-position.
• the indazolyl, benzothiazolyl, benzoisothiazolyl, and benzisoxazolyl groups of A can be attached to the remainder of the structure via any suitable attachment point.
• the following subformulas illustrate some of the preferred attachments between the indazole, benzothiazole, benzoisothiazole, and benzisoxazole groups and the remainder of the structure.
• Alkyl throughout means a straight-chain or branched-chain aliphatic hydrocarbon radical having preferably 1 to 4 carbon atoms. Suitable alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.
• Alkenyl throughout means a straight-chain or branched-chain aliphatic hydrocarbon radical having preferably 2 to 6 carbon atoms. Suitable alkenyl groups include but are not limited to ethenyl, propenyl, butenyl, and pentenyl.
• Alkynyl throughout means a straight-chain or branched-chain aliphatic hydrocarbon radical having preferably 2 to 6 carbon atoms. Suitable alkynyl groups include but are not limited to ethyne, propyne, butyne, etc.
• Alkoxy means alkyl-O— groups in which the alkyl portion preferably has 1 to 4 carbon atoms. Suitable alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, and sec-butoxy.
• Alkylthio means alkyl-S— groups in which the alkyl portion preferably has 1 to 4 carbon atoms. Suitable alkylthio groups include but are not limited to methylthio and ethylthio.
• Cycloalkyl means a cyclic, bicyclic or tricyclic saturated hydrocarbon radical having 3 to 7 carbon atoms.
• Suitable cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
• Other suitable cycloalkyl groups include but are not limited to spiropentyl, bicyclo[2.1.0]pentyl, and bicyclo[3.1.0]hexyl.
• Cycloalkoxy means cycloalkyl-O— groups in which the cycloalkyl portion preferably is a cyclic, bicyclic or tricyclic saturated hydrocarbon radical having 3 to 7 carbon atoms.
• Cycloalkylalkyl groups contain 4 to 7 carbon atoms. Suitable cycloalkylalkyl groups include but are not limited to, for example, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, and cyclopentylmethyl.
• Cycloalkylalkoxy groups contain 4 to 7 carbon atoms. Suitable cycloalkylalkoxy groups include but are not limited to, for example, cyclo-propylmethyloxy, cyclopropylethyloxy, cyclobutylmethyloxy, and cyclo-pentylmethyloxy.
• the cycloalkyl and cycloalkylalkyl groups can be substituted by C 1-4 -alkyl, C 1-4 -alkoxy, hydroxyl, amino, monoalkylamino having 1 to 4 carbon atoms, and/or dialklyamino in which each alkyl group has 1 to 4 carbon atoms.
• Aryl as a group or substituent per se or as part of a group or substituent, refers to an aromatic carbocyclic radical containing 6 to 10 carbon atoms, unless indicated otherwise. Suitable aryl groups include but are not limited to phenyl, napthyl and biphenyl.
• Substituted aryl groups include the above-described aryl groups which are substituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, phenoxy, and acyloxy (e.g., acetoxy).
• Heterocyclic groups refer to saturated, partially saturated and fully unsaturated heterocyclic groups having one, two or three rings and a total number of 5 to 10 ring atoms wherein at least one of the ring atoms is an N, O or S atom.
• the heterocyclic group contains 1 to 3 hetero-ring atoms selected from N, O and S.
• Suitable saturated and partially saturated heterocyclic groups include, but are not limited to dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl and the like.
• Suitable heteroaryl groups include but are not limited to furyl, thienyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, naphthyridinyl and the like.
• heterocyclic groups are 2-furyl, 3-furyl, 2-quinolinyl, 1,3-benzodioxyl, 2-thienyl, 3-thienyl, 1,3-thiazoly-2-yl, 1,3-oxazol-2-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, 2-benzofuranyl, 2-benzothiophenyl, 3-thienyl, 2,3-dihydro-5-benzofuranyl, 4-indoyl, 4-pyridyl, 3-quinolinyl, 4-quinolinyl, 1,4-benzodioxan-6-yl, 3-indoyl, 2-pyrrolyl, tetrahydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, 5-indolyl, 1,5-benzoxepin-8-yl, 3-pyridyl, 6-coumarinyl
• Substituted heterocyclic groups refer to the heterocyclic groups described above, which are substituted in one or more places by, for example, halogen, aryl, alkyl, alkoxy, cyano, trifluoromethyl, nitro, oxo, amino, alkylamino, and dialkylamino.
• Radicals that are substituted one or more times preferably have 1 to 3 substituents, especially 1 or 2 substituents of the exemplified substituents.
• Halogenated radicals such as halogenated alkyls are preferably fluorinated and include but are not limited to perhalo radicals such as trifluoromethyl.
• R 6 and R 7 when R is NR 6 R 7 , at least one of R 6 and R 7 is alkyl having 2 to 4 carbon atoms, alkoxyalkyl having 2 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, or cycloalkylalkyl having 4 to 7 carbon atoms, or R 6 and R 7 together are an alkylene group containing 4-6 carbon atoms which forms a ring with the N atom.
• R is not NR 6 R 7 .
• A is a radical according to formulas (a), (b) or (c), and at least one of R 1 , R 3 , or R 4 is H, F, Cl, Br, I, OH, CN, nitro, NH 2 , COH, NR 6 R 7 , carboxy, CONR 6 R 7 , NR 2 COR 8 , NR 2 COOR 8 , NR 2 CSR 8 , NR 2 CONR 2 R 9 , NR 2 CSNR 2 R 9 , NR 2 SO 2 R 10 , NR 2 CONR 6 R 7 , NR 2 CSNR 6 R 7 , NR 2 R 9 , SO 2 R 10 , SOR 10 , alkyl having 1 to 4 carbon atoms, fluorinated alkyl having 1 to 4 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, wherein the alkyl,
• At least one of R 1 , R 3 , or R 4 is
• the compounds are selected from formula I in which A is of formulae (a) or (c), X is O, R 2 is H or alkyl (e.g., CH 3 ), and R 1 and R 4 are each F, Cl, CN, NO 2 , NH 2 , fluorinated alkyl (e.g., CF 3 ), alkoxy (e.g., OCH 3 ), fluorinated alkoxy (e.g., OCF 3 ), fluorinated hydroxyalkyl (e.g., 2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl), alkynyl (e.g., ethynyl, propynyl), cycloalkyl, cycloalkylalkoxy, Ar, Ar-alkynyl (e.g., phenylacetylene), or Het.
• A is of formulae (a) or (c)
• X is O
• R 2 is H
• R 1 and R 4 are each selected from F, Cl, CN, NO 2 , NH 2 , CF 3 , OCH 3 , OC 2 H 5 , OCF 3 , 2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl, ethynyl, propynyl, pentynyl, cyclopentyl, cyclohexyl, cyclopropylmethoxy, phenyl, phenylethynyl, dihydropyranyl (e.g., 3,6-dihydro-2H-pyran-4-yl), thiazolyl (e.g., 1,3-thiazol-2-yl), oxazolyl (e.g., 1,3-oxazol-2-yl), pyrrolidinyl (e.g., pyrrolidin-1-yl), piperidinyl (e.g.
• R 4 can also be selected from CN, alkoxy, fluorinated alkoxy, and cycloalkylalkoxy, such as CN, OCH 3 , OC 2 H 5 , OCF 3 , and cyclopropylmethoxy.
• the compounds are selected from formulae Ia or Ij wherein R 2 is H or alkyl (e.g., CH 3 ), and R 1 and R 4 are each F, Cl, CN, NO 2 , NH 2 , fluorinated alkyl (e.g., CF 3 ), alkoxy (e.g., OCH 3 ), fluorinated alkoxy (e.g., OCF 3 ), fluorinated hydroxyalkyl (e.g., 2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl), alkynyl (e.g., ethynyl, propynyl), cycloalkyl, cycloalkylalkoxy, Ar, Ar-alkynyl (e.g., phenylacetylene), or Het.
• R 2 is H or alkyl (e.g., CH 3 )
• R 1 and R 4 are each F, Cl, CN, NO 2
• R 1 and R 4 are each selected from F, Cl, CN, NO 2 , NH 2 , CF 3 , OCH 3 , OC 2 H 5 , OCF 3 , 2,2,2,-trifluoro-1-hydroxyl-1-(trifluoromethyl)ethyl, ethynyl, propynyl, pentynyl, cyclopentyl, cyclohexyl, cyclopropylmethoxy, phenyl, phenylethynyl, dihydropyranyl (e.g., 3,6-dihydro-2H-pyran 55 -4-yl), thiazolyl (e.g., 1,3-thiazol-2-yl), oxazolyl (e.g., 1,3-oxazol-2-yl), pyrrolidinyl (e.g., pyrrolidin-1-yl), piperidinyl (e.g.
• R 4 can also be selected from CN, alkoxy, fluorinated alkoxy, and cycloalkylalkoxy, such as CN, OCH 3 , OC 2 H 5 , OCF 3 , and cyclopropylmethoxy.
• At least one R 1 , R 3 or R 4 is COH, NR 6 R 7 wherein at least one of R 6 and R 7 is other than alkyl, or NR 2 COOR 8 .
• At least one R 1 , R 3 or R 4 is selected from the following formulas
• the compounds of Formulas I-IV exhibit 2-3 of substituents R 1 , R 3 , or R 4 .
• R 2 is fluorinated alkyl having 1 to 4 carbon atoms.
• At least one R 6 and R 7 is alkoxyalkyl having 2 to 8 carbon atoms.
• the compound exhibits at least one R 9 group that is Ar-alkyl wherein the alkyl portion has 1 to 4 carbon atoms.
• the compound exhibits at least one Het that is a heterocyclic group, which is fully saturated, partially saturated or fully unsaturated, having 5 to 10 ring atoms in which at least 1 ring atom is a N, O or S atom, and which is substituted by at least one substituent selected from OH, alkoxycarbonylalkyl having 3 to 8 carbon atoms, and piperidinylethyl.
• the compound of formulas I-IV is selected from (wherein compounds in their salt forms can also be in their non-salt forms):
• the compound of formulas I-IV is selected from (wherein compounds in their salt forms can also be in their non-salt forms):
• the compound of formulas I-IV is selected from (wherein compounds in their salt forms can also be in their non-salt forms):
• Preferred aspects include pharmaceutical compositions comprising a compound of this invention and a pharmaceutically acceptable carrier and, optionally, another active agent as discussed below; a method of stimulating or activating inhibiting alpha-7 nicotinic receptors, e.g., as determined by a conventional assay or one described herein, either in vitro or in vivo (in an animal, e.g., in an animal model, or in a mammal or in a human); a method of treating a neurological syndrome, e.g., loss of memory, especially long-term memory, cognitive impairment or decline, memory impairment, etc. method of treating a disease state modulated by nicotinic alpha-7 activity, in a mammal, e.g., a human, e.g., those mentioned herein.
• a mammal e.g., a human, e.g., those mentioned herein.
• the compounds of the present invention may be prepared conventionally. Some of the known processes that can be used are described below. All starting materials are known or can be conventionally prepared from known starting materials.
• Acids that were used in the preparation of the bicyclobase amide were commercially available or were prepared by known procedures described in the literature or as described below.
• indazole-3-carboxylic acid was commercially available.
• Positional isomers of indazole carboxylic acid were prepared from the requisite bromo-2-methylanilines by diazotization followed by metal-halogen exchange and trapping with carbon dioxide (Se e.g., DeLucca, G. V. Substituted 2H-1,3-Diazapin-2-one Useful as an HIV Protease Inhibitor, U.S. Pat. No. 6,313,110 B1, Nov. 6, 2001; and Sun, J. H.; Teleha, C. A.; Yan, J.
• Some substituted indazole-3-acids were prepared by modifying existing indazole acids or esters.
• 5-nitroindazole-3-acid was prepared by nitration of indazole-3-acid (Kamm, O.; Segur, J. B. Org. Syn. Coll . Vol 1. 1941, 372).
• 6-Nitroindazole-3-acid was prepared from 3-iodo-6-nitroindazole using copper (I) cyanide followed by hydrolysis.
• Some non-aromatic heterocyclic derivatives were prepared from the bromides by metal-halogen exchange, trapping of indazole aryllithiums with ketones, followed by reduction or acid mediated elimination.
• Aromatic substituted indazole-3-acids were prepared from the bromides via palladium mediated cross-coupling with boronic acids or aryl zinc reagents (Reeder, M. R.; et. al. Org. Proc. Res. Devel. 2003, 7, 696).
• 4-Bromo-5-methoxyindazole- and 7-bromo-6-methoxyindazole-3-carboxylic acids were prepared from the corresponding methoxyindazole-3-carboxylates by bromination and saponification.
• 4-Fluoro-5-methoxyindazole- and 7-fluoro-6-methoxyindazole-3-carboxylic acids were prepared from the corresponding methoxyindazole-3-carboxylates by fluorination and saponification.
• 5-Bromo-4-nitroindazole- and 6-bromo-7-nitroindazole-3-carboxylic acids were prepared from the corresponding bromoindazole-3-carboxylates by nitration and saponification. Subjecting the nitro bromides to hydrogenolysis provided 4-aminoindazole- and 7-aminoindazole-3-carboxylic acids.
• N-1-Alkylated indazole-3-carboxylic acids were prepared from the corresponding indazole esters by standard alkylation procedures.
• N-1-Arylated indazole-3-carboxylic acids were prepared from the corresponding indazole esters by copper mediated cross couplings with boronic acids.
• Phenol derivatives were prepared from the corresponding methoxy acids using boron tribromide.
• Some substituted indazole-3-acids were prepared from simple benzene derivatives.
• 5-difluoromethoxyindazole-3-acid was prepared from 3-bromo-4-nitrophenol by reaction with ethyl difluoroacetate, reaction with diethyl malonate, decarboxylative saponification, esterification, reduction of the nitro group, and diazotization.
• 6-Difluoromethoxyindazole-3-acid was prepared in a similar manner from 2-bromo-5-difluoromethoxynitrobenzene.
• the 2-bromo-5-difluoromethoxynitrobenzene used in that preparation was prepared from 4-nitrophenol by ether formation, nitro reduction with concomitant protection as the amide, nitration, amide hydrolysis, and a Sandmeyer reaction with copper (I) bromide.
• 6-Benzyloxyindazole-3-carboxylic acid and ester was prepared from 4-methoxynitrobenzene by nitro reduction with concomitant protection as the amide, nitration, amide hydrolysis, Sandmeyer reaction with copper (I) bromide, and demethylation.
• the phenol was alkylated with benzyl bromide and the arylbromide was subjected to reaction with diethyl malonate, decarboxylative saponification, esterification, reduction of the nitro group, and diazotization.
• the 5-benzyloxy analog was prepared in a similar manner from 4-benzyloxy-2-bromonitrobenzene (Parker, K. A.; Mindt, T. L. Org. Lett. 2002, 4, 4265.)
• the benzyl group was removed by hydrogenolysis and the resulting phenol was transformed to ether derivatives via either alkylation or Mitsunobu reaction conditions.
• 4-Methoxyindazole acid was prepared from 4-methoxyaniline by amide formation, nitration, amide hydrolysis, Sandmeyer reaction with copper (I) bromide, nitro reduction, isatin formation and rearrangement to the indazole, followed by hydrogenolytic removal of the bromine.
• benzisoxazole-, benzisoxazole-, and benzothiazolecarboxylic acids were prepared using similar strategies outlined for the indazole acids.
• ethyl 6-bromobenzisoxazole-3-carboxylate was prepared from 2,5-dibromonitrobenzene by reaction with diethyl malonate, saponification and decarboxylation, and reaction with isoamylnitrite.
• Ethyl benzisoxazole-3-carboxylate was obtained by hydrogenolysis of the 6-bromo derivative.
• 4-Benzothiazolecarboxylic acid was prepared from 2-amino-4-chloro-benzothiazole by reaction with isoamyl nitrite followed by metal-halogen exchange and trapping with carbon dioxide.
• 5-Benzothiazolecarboxylic acid was prepared from 4-chloro-3-nitrobenzoic acid by reaction with Na 2 S and sodium hydroxide followed by reduction with zinc in formic acid.
• 3-Benzisothiazolecarboxylic acid was prepared from thiophenol by reaction with oxalyl chloride and aluminum chloride followed by treatment with hydroxylamine, hydrogen peroxide, and sodium hydroxide.
• the bicycloamines, 3-aminoquinuclidine and the R- and S-enantiomers thereof, used in the preparation of the bicyclobase amides were commercially available.
• the N-alkylated quinuclidines were prepared by acylation of 3-aminoquinuclidine followed by reduction of the amide.
• 3-Aminomethylquinuclidine was prepared from 3-quinuclidinone by the action of p-tolylsulfonylmethyl isocyanide followed by hydrogenation of the nitrile.
• the bicyclobase amides were prepared from the acids and the bicycloamines using standard peptide coupling agents, such as HBTU, HATU, or HOBt and EDCI, or by converting the acids to the corresponding acid chloride and then reaction with the bicycloamine (Macor, J. E.; Gurley, D.; Lanthom, T.; Loch, J.; Mack, R. A.; Mullen, G.; Tran, O.; Wright, N.; and J. E. Macor et al., “The 5-HT3-Antagonwast Tropisetron (ICS 205-930) was a Potent and Selective ⁇ -7 Nicotinic Receptor Partial Agonist,” Bioorg. Med. Chem. Lett. 2001, 9, 319-321). The couplings were generally performed at room temperatures for 18-24 hours. The resultant adducts were isolated and purified by standard techniques, such as chromatography or recrystallization, practiced by those skilled in the art.
• the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
• appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid.
• Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization.
• the optically active bases or acids are then liberated from the separated diastereomeric salts.
• a different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivation, optimally chosen to maximize the separation of the enantiomers.
• Suitable chiral HPLC columns are manufactured by Diacel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable.
• Enzymatic separations, with or without derivitization, are also useful.
• the optically active compounds of Formulas I-IV can likewise be obtained by utilizing optically active starting materials in chiral synthesis processes under reaction conditions which do not cause racemization.
• the compounds can be used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C.
• the compounds are deuterated.
• Such deuterated forms can be made the procedure described in U.S. Pat. Nos. 5,846,514 and 6,334,997.
• deuteration can improve the efficacy and increase the duration of action of drugs.
• Deuterium substituted compounds can be synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] (2000), 110 pp. CAN 133:68895 AN 2000:473538 CAPLUS; Kabalka, George W.; Varma, Rajender S. The synthesis of radiolabeled compounds via organometallic intermediates. Tetrahedron (1989), 45(21), 6601-21, CODEN: TETRAB ISSN:0040-4020. CAN 112:20527 AN 1990:20527 CAPLUS; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem. (1981), 64(1-2), 9-32. CODEN: JRACBN ISSN:0022-4081, CAN 95:76229 AN 1981:476229 CAPLUS.
• the present invention also relates to useful forms of the compounds as disclosed herein, such as pharmaceutically acceptable salts or prodrugs of all the compounds of the present invention for which salts or prodrugs can be prepared.
• Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, and carbonic acid.
• Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and choline salts.
• an appropriate base e.g., sodium, potassium, calcium, magnesium, ammonium, and choline salts.
• acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
• alkali and alkaline earth metal salts can be prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
• acid salts that can be obtained by reaction with inorganic or organic acids: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, camphorates, digluconates, cyclopentanepropionates, dodecylsulfates, ethanesulfonates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides, hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates, methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates, palmoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates,
• the salts formed are pharmaceutically acceptable for administration to mammals.
• pharmaceutically unacceptable salts of the compounds are suitable as intermediates, for example, for isolating the compound as a salt and then converting the salt back to the free base compound by treatment with an alkaline reagent.
• the free base can then, if desired, be converted to a pharmaceutically acceptable acid addition salt.
• the compounds of the invention can be administered alone or as an active ingredient of a formulation.
• the present invention also includes pharmaceutical compositions of compounds of Formulas I-IV, containing, for example, one or more pharmaceutically acceptable carriers.
• the compounds of the present invention can be administered to anyone needing stimulation of alpha-7 receptors.
• Administration may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intraveneously, intramuscularly, intrasternally and by infusion) by inhalation, rectally, vaginally, topically and by ocular administration.
• solid oral dosage forms can be used for administering compounds of the invention including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders.
• the compounds of the present invention can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and excipients known in the art, including but not limited to suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like.
• Time release capsules, tablets and gels are also advantageous in administering the compounds of the present invention.
• liquid oral dosage forms can also be used for administering compounds of the inventions, including aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs.
• Such dosage forms can also contain suitable inert diluents known in the art such as water and suitable excipients known in the art such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention.
• the compounds of the present invention may be injected, for example, intravenously, in the form of an isotonic sterile solution. Other preparations are also possible.
• Suppositories for rectal administration of the compounds of the present invention can be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols.
• a suitable excipient such as cocoa butter, salicylates and polyethylene glycols.
• Formulations for vaginal administration can be in the form of a pessary, tampon, cream, gel, paste, foam, or spray formula containing, in addition to the active ingredient, such suitable carriers as are known in the art.
• the pharmaceutical composition can be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear or nose. Topical administration may also involve transdermal administration via means such as transdermal patches.
• Aerosol formulations suitable for administering via inhalation also can be made.
• the compounds according to the invention can be administered by inhalation in the form of a powder (e.g., micronized) or in the form of atomized solutions or suspensions.
• the aerosol formulation can be placed into a pressurized acceptable propellant.
• the compounds can be administered as the sole active agent or in combination with other pharmaceutical agents such as other agents used in the treatment of cognitive impairment and/or memory loss, e.g., other ⁇ -7 agonists, PDE4 inhibitors, calcium channel blockers, muscarinic m1 and m2 modulators, adenosine receptor modulators, amphakines NMDA-R modulators, mGluR modulators, dopamine modulators, serotonin modulators, canabinoid modulators, and cholinesterase inhibitors (e.g., donepezil, rivastigimine, and glanthanamine).
• each active ingredient can be administered either in accordance with their usual dosage range or a dose below their usual dosage range.
• the compounds of the invention can be used in conjunction with “positive modulators” which enhance the efficacy of nicotinic receptor agonists. See, e.g., the positive modulators disclosed in WO 99/56745, WO 01/32619, and WO 01/32622. Such combinational therapy can be used in treating conditions/diseases associated with reduced nicotinic transmission.
• the compounds may be used in conjunction with compounds that bind to A ⁇ peptides and thereby inhibit the binding of the peptides to ⁇ 7nACh receptor subtypes. See, e.g., WO 99/62505.
• the present invention further includes methods of treatment that involve activation of ⁇ -7 nicotinic receptors.
• the present invention includes methods of selectively activating/stimulating ⁇ -7 nicotinic receptors in a patient (e.g., a mammal such as a human) wherein such activation/stimulation has a therapeutic effect, such as where such activation may relieve conditions involving neurological syndromes, such as the loss of memory, especially long-term memory.
• Such methods comprise administering to a patient (e.g., a mammal such as a human) in need thereof, an effective amount of a compound of Formulas I-IV, alone or as part of a formulation, as disclosed herein.
• a method of treating a patient e.g., a mammal such as a human
• a disease state e.g., memory impairment
• the disease state involves decreased nicotinic acetylcholine receptor activity.
• a method for the treatment or prophylaxis of a disease or condition resulting from dysfunction of nicotinic acetylcholine receptor transmission in a patient comprising administering an effective amount of a compound according to Formulas I-IV.
• a method for the treatment or prophylaxis of a disease or condition resulting from defective or malfunctioning nicotinic acetylcholine receptors, particularly ⁇ 7nACh receptors, in a patient comprising administering an effective amount of a compound according to Formulas I-IV.
• a method for the treatment or prophylaxis of a disease or condition resulting from suppressed nicotinic acetylcholine receptor transmission in a patient comprising administering an amount of a compound according to Formulas I-IV effective to activate ⁇ 7nACh receptors.
• a method for the treatment or prophylaxis of a psychotic disorder, a cognition impairment (e.g., memory impairment), or neurodegenerative disease in a patient comprising administering an effective amount of a compound according to Formulas I-IV.
• a method for the treatment or prophylaxis of a disease or condition resulting from loss of cholinergic synapses in a patient comprising administering an effective amount of a compound according to Formulas I-IV.
• a method for the treatment or prophylaxis of a neurodegenerative disorder by activation of ⁇ 7nACh receptors in a patient comprising administering an effective amount of a compound according to Formulas I-IV.
• a method for protecting neurons in a patient comprising administering an effective amount of a compound according to Formulas I-IV.
• a method for the treatment or prophylaxis of a neurodegenerative disorder by inhibiting the binding of A ⁇ peptides to ⁇ 7nACh receptors in a patient (e.g., a mammal such as a human) comprising administering an effective amount of a compound according to Formulas I-IV.
• a method for protecting neurons in a patient comprising administering an effective amount of a compound according to Formulas I-IV.
• a method for alleviating inhibition of cholinergic function induced by A ⁇ peptides in a patient comprising administering an effective amount of a compound according to Formulas I-IV.
• a subject or patient in whom administration of the therapeutic compound is an effective therapeutic regimen for a disease or disorder is preferably a human, but can be any animal, including a laboratory animal in the context of a clinical trial or screening or activity experiment.
• the methods, compounds and compositions of the present invention are particularly suited to administration to any animal, particularly a mammal, and including, but by no means limited to, humans, domestic animals, such as feline or canine subjects, farm animals, such as but not limited to bovine, equine, caprine, ovine, and porcine subjects, wild animals (whether in the wild or in a zoological garden), research animals, such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., avian species, such as chickens, turkeys, songbirds, etc., i.e., for veterinary medical use.
• the compounds of the present invention are nicotinic alpha-7 ligands, preferably agonists, especially partial agonists, for the alpha-7 nicotinic acetylcholine receptor.
• Assays for determining nicotinic acetylcholine activity are known within the art. See, e.g., Davies, A. R., et al., Characterisation of the binding of [ 3 H]methyllycaconitine: a new radioligand for labelling alpha 7- type neuronal nicotinic acetylcholine receptors . Neuropharmacology, 1999. 38(5): p. 679-90.
• Nicotinic acetylcholine receptors are ligand-gastrol ion-channel receptors that are composed of five subunit proteins which form a central ion-conducting pore.
• Nicotinic acetylcholine receptors are ligand-gastrol ion-channel receptors that are composed of five subunit proteins which form a central ion-conducting pore.
• neuronal nACh receptor subunits ⁇ 2- ⁇ 9 and ⁇ 2- ⁇ 4
• There are also five further subunits expressed in the peripheral nervous system ⁇ 1, ⁇ 1, ⁇ , ⁇ , ⁇ ).
• the nACh receptor subtypes can be homopentameric or heteropentameric.
• the subtype which has received considerable attention is the homopentameric ⁇ 7 receptor subtype formed from five ⁇ 7 subunits.
• the ⁇ 7nACh receptors exhibit a high affinity for nicotine (agonist) and for ⁇ -bungarotoxin (antagonist).
• the ⁇ 7nACh receptor agonists can be useful in the treatment of psychotic diseases, neurodegenerative diseases, and cognitive impairments, among other things. While nicotine is a known agonist, there is a need for the development of other ⁇ 7nACh receptor agonists, especially selective agonists, which are less toxic or exhibit fewer side effects than nicotine.
• the compound anabaseine i.e., 2-(3-pyridyl)-3,4,5,6-tetrahydropyridine is a naturally occurring toxin in certain marine worms (nemertine worms) and ants. See, e.g., Kem et al., Toxicon, 9:23, 1971.
• Anabaseine is a potent activator of mammalian nicotinic receptors. See, e.g., Kem, Amer. Zoologist, 25, 99, 1985.
• anabaseine analogs such as anabasine and DMAB (3-[4-(dimethylamino)benzylidene]-3,4,5,6-tetrahydro-2′,3′-bipyridine) are also known nicotinic receptor agonists. See, e.g., U.S. Pat. No. 5,602,257 and WO 92/15306.
• One particular anabaseine analog, (E-3-[2,4-dimethoxy-benzylidene]-anabaseine, also known as GTS-21 and DMXB is a selective partial ⁇ 7nACh receptor agonist that has been studied extensively.
• abnormal sensory inhibition is a sensory processing deficit in schizophrenics and GTS-21 has been found to increase sensory inhibition through interaction with ⁇ 7nACh receptors. See, e.g., Stevens et al., Psychopharmacology, 136: 320-27 (1998).
• Tropisetron i.e., 1 ⁇ H, 5 ⁇ H-tropan-3 ⁇ -yl indole-3-carboxylate. See J. E. Macor et al., The 5- HT 3- Antagonist Tropisetron ( ICS 205-930) is a Potent and Selective A 7 Nicotinic Receptor Partial Agonist . Bioorg. Med. Chem. Lett. 2001, 319-321).
• Agents that bind to nicotinic acetylcholine receptors have been indicated as useful in the treatment and/or prophylaxis of various diseases and conditions, particularly psychotic diseases, neurodegenerative diseases involving a dysfunction of the cholinergic system, and conditions of memory and/or cognition impairment, including, for example, schizophrenia, anxiety, mania, depression, manic depression [examples of psychotic disorders], Tourette's syndrome, Parkinson's disease, Huntington's disease [examples of neurodegenerative diseases], cognitive disorders (such as Alzheimer's disease, Lewy Body Dementia, Amyotrophic Lateral Sclerosis, memory impairment, memory loss, cognition deficit, attention deficit, Attention Deficit Hyperactivity Disorder), and other uses such as treatment of nicotine addiction, inducing smoking cessation, treating pain (i.e., analgesic use), providing neuroprotection, and treating jetlag.
• psychotic diseases including, for example, schizophrenia, anxiety, mania, depression, manic depression [examples of psychotic disorders],
• a method of treating a patient, especially a human, suffering from psychotic diseases, neurodegenerative diseases involving a dysfunction of the cholinergic system, and conditions of memory and/or cognition impairment including, for example, schizophrenia, anxiety, mania, depression, manic depression [examples of psychotic disorders], Tourette's syndrome, Parkinson's disease, Huntington's disease [examples of neurodegenerative diseases], and/or cognitive disorders (such as Alzheimer's disease, Lewy Body Dementia, Amyotrophic Lateral Sclerosis, memory impairment, memory loss, cognition deficit, attention deficit, Attention Deficit Hyperactivity Disorder) comprising administering to the patient an effective amount of a compound according to Formulas I-IV.
• psychotic diseases including, for example, schizophrenia, anxiety, mania, depression, manic depression [examples of psychotic disorders], Tourette's syndrome, Parkinson's disease, Huntington's disease [examples of neurodegenerative diseases]
• cognitive disorders such as Alzheimer's disease, Lewy Body Dementia,
• Neurodegenerative disorders included within the methods of the present invention include, but are not limited to, treatment and/or prophylaxis of Alzheimer's diseases, Pick's disease, diffuse Lewy Body disease, progressive supranuclear palsy (Steel-Richardson syndrome), multisystem degeneration (Shy-Drager syndrome), motor neuron diseases including amyotrophic lateral sclerosis, degenerative ataxias, cortical basal degeneration, ALS-Parkinson's-Dementia complex of Guam, subacute sclerosing panencephalitis, Huntington's disease, Parkinson's disease, synucleinopathies, primary progressive aphasia, striatonigral degeneration, Machado-Joseph disease/spinocerebellar ataxia type 3, olivopontocerebellar degenerations, Gilles De La Tourette's disease, bulbar, pseudobulbar palsy, spinal muscular atrophy, spinobulbar muscular atrophy (Kennedy's disease),
• ⁇ 7nACh receptor agonists such as the compounds of the present invention can be used to treat age-related dementia and other dementias and conditions with memory loss including age-related memory loss, senility, vascular dementia, diffuse white matter disease (Binswanger's disease), dementia of endocrine or metabolic origin, dementia of head trauma and diffuse brain damage, dementia pugilistica and frontal lobe dementia. See, e.g., WO 99/62505.
• a method of treating a patient, especially a human, suffering from age-related dementia and other dementias and conditions with memory loss comprising administering to the patient an effective amount of a compound according to Formulas I-IV.
• the present invention includes methods of treating patients suffering from memory impairment due to, for example, mild cognitive impairment due to aging, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility, multiinfarct dementia and other neurological conditions, as well as HIV and cardiovascular diseases, comprising administering an effective amount of a compound according to Formulas I-IV.
• Amyloid precursor protein (APP) and A ⁇ peptides derived therefrom, e.g., A ⁇ 1-40 , A ⁇ 1-42 , and other fragments, are known to be involved in the pathology of Alzhemier's disease.
• the A ⁇ 1-42 peptides are not only implicated in neurotoxicity but also are known to inhibit cholinergic transmitter function.
• a ⁇ peptides bind to ⁇ 7nACh receptors.
• agents which block the binding of the A ⁇ peptides to ⁇ -7 nAChRs are useful for treating neurodegenerative diseases. See, e.g., WO 99/62505.
• stimulation ⁇ 7nACh receptors can protect neurons against cytotoxicity associated with A ⁇ peptides. See, e.g., Kihara, T. et al., Ann. Neurol., 1997, 42, 159.
• a method of treating and/or preventing dementia in an Alzheimer's patient which comprises administering to the subject a therapeutically effective amount of a compound according to Formulas I-IV to inhibit the binding of an amyloid beta peptide (preferably, A ⁇ 1-42 ) with nACh receptors, preferable ⁇ 7nACh receptors, most preferably, human ⁇ 7nACh receptors (as well as a method for treating and/or preventing other clinical manifestations of Alzheimer's disease that include, but are not limited to, cognitive and language deficits, apraxias, depression, delusions and other neuropsychiatric symptoms and signs, and movement and gait abnormalities).
• an amyloid beta peptide preferably, A ⁇ 1-42
• nACh receptors preferable ⁇ 7nACh receptors
• human ⁇ 7nACh receptors preferably, human ⁇ 7nACh receptors
• the present invention also provides methods for treating other amyloidosis diseases, for example, hereditary cerebral angiopathy, normeuropathic hereditary amyloid, Down's syndrome, macroglobulinemia, secondary familial Mediterranean fever, Muckle-Wells syndrome, multiple myeloma, pancreatic- and cardiac-related amyloidosis, chronic hemodialysis anthropathy, and Finnish and Iowa amyloidosis.
• other amyloidosis diseases for example, hereditary cerebral angiopathy, normeuropathic hereditary amyloid, Down's syndrome, macroglobulinemia, secondary familial Mediterranean fever, Muckle-Wells syndrome, multiple myeloma, pancreatic- and cardiac-related amyloidosis, chronic hemodialysis anthropathy, and Finnish and Iowa amyloidosis.
• nicotinic receptors have been implicated as playing a role in the body's response to alcohol ingestion.
• agonists for ⁇ 7nACh receptors can be used in the treatment of alcohol withdrawal and in anti-intoxication therapy.
• a method of treating a patient for alcohol withdrawal or treating a patient with anti-intoxication therapy comprising administering to the patient an effective amount of a compound according to Formulas I-IV.
• Agonists for the ⁇ 7nACh receptor subtypes can also be used for neuroprotection against damage associated with strokes and ischemia and glutamate-induced excitotoxicity.
• a method of treating a patient to provide for neuroprotection against damage associated with strokes and ischemia and glutamate-induced excitotoxicity comprising administering to the patient an effective amount of a compound according to Formulas I-IV.
• agonists for the ⁇ 7nACh receptor subtypes can also be used in the treatment of nicotine addiction, inducing smoking cessation, treating pain, and treating jetlag, obesity, diabetes, and inflammation.
• a method of treating a patient suffering from nicotine addiction, pain, jetlag, obesity and/or diabetes, or a method of inducing smoking cessation in a patient comprising administering to the patient an effective amount of a compound according to Formulas I-IV.
• the inflammatory reflex is an autonomic nervous system response to an inflammatory signal.
• the autonomic nervous system responds through the vagus nerve by releasing acetylcholine and activating nicotinic ⁇ 7 receptors on macrophages. These macrophages in turn release cytokines. Dysfunctions in this pathway have been linked to human inflammatory diseases including rheumatoid arthritis, diabetes and sepsis. Macrophages express the nicotinic ⁇ 7 receptor and it is likely this receptor that mediates the cholinergic anti-inflammatory response.
• compounds with affinity for the ⁇ 7nACh receptor on macrophages may be useful for human inflammatory diseases including rheumatoid arthritis, diabetes and sepsis. See, e.g., Czura, C J et al., J. Intern. Med., 2005, 257(2), 156-66.
• a method of treating a patient e.g., a mammal, such as a human
• an inflammatory disease such as, but not limited to, rheumatoid arthritis, diabetes or sepsis
• administering comprising administering to the patient an effective amount of a compound according to Formulas I-IV.
• labeled derivatives of the compounds of Formulas I-IV can be used in neuroimaging of the receptors within, e.g., the brain.
• labeled agents in vivo imaging of the receptors can be performed using, e.g., PET imaging.
• the condition of memory impairment is manifested by impairment of the ability to learn new information and/or the inability to recall previously learned information.
• Memory impairment is a primary symptom of dementia and can also be a symptom associated with such diseases as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, HIV, cardiovascular disease, and head trauma as well as age-related cognitive decline.
• a method of treating a patient suffering from, for example, mild cognitive impairment (MCI), vascular dementia (VaD), age-associated cognitive decline (AACD), amnesia associated w/open-heart-surgery, cardiac arrest, and/or general anesthesia memory deficits from early exposure of anesthetic agents, sleep deprivation induced cognitive impairment, chronic fatigue syndrome, narcolepsy, AIDS-related dementia, epilepsy-related cognitive impairment, Down's syndrome, Alcoholism related dementia, drug/substance induced memory impairments, Dementia Puglistica (Boxer Syndrome), and animal dementia (e.g., dogs, cats, horses, etc.) comprising administering to the patient an effective amount of a compound according to Formulas I-IV.
• MCI mild cognitive impairment
• VaD vascular dementia
• AACD age-associated cognitive decline
• amnesia associated w/open-heart-surgery cardiac arrest
• general anesthesia memory deficits from early exposure of anesthetic agents
• the dosages of the compounds of the present invention depend upon a variety of factors including the particular syndrome to be treated, the severity of the symptoms, the route of administration, the frequency of the dosage interval, the particular compound utilized, the efficacy, toxicology profile, pharmacokinetic profile of the compound, and the presence of any deleterious side-effects, among other considerations.
• the compounds of the invention can be administered to patients, e.g., mammals, particularly humans, at typical dosage levels customary for ⁇ -7 nicotinic receptor agonists such as the known ⁇ -7 nicotinic receptor agonist compounds mentioned above.
• the compounds can be administered, in single or multiple doses, by oral administration at a dosage level of, for example, 0.0001-10 mg/kg/day, e.g., 0.01-10 mg/kg/day.
• Unit dosage forms can contain, for example, 1-200 mg of active compound.
• the compounds can be administered in single or multiple dosages.
• buffers, media, reagents, cells, culture conditions and the like are not intended to be limiting, but are to be read so as to include all related materials that one of ordinary skill in the art would recognize as being of interest or value in the particular context in which that discussion is presented. For example, it is often possible to substitute one buffer system or culture medium for another and still achieve similar, if not identical, results. Those of skill in the art will have sufficient knowledge of such systems and methodologies so as to be able, without undue experimentation, to make such substitutions as will optimally serve their purposes in using the methods and procedures disclosed herein.
• Analytical HPLC was performed on 4.6 mm ⁇ 100 mm Xterra RP 18 3.5 ⁇ columns using a gradient of 20/80 to 80/20 water (0.1% formic acid)/acetonitrile (0.1% formic acid) over 6 min.
• Preparative HPLC was performed on 30 mm ⁇ 100 mm Xtera Prep RP 18 5 ⁇ columns using an 8 min gradient of 95/5 to 20/80 water (0.1% formic acid)/acetonitrile (0.1% formic acid).
• Procedure 1 provides a method of preparation of 1,3-benzothiazole carboxylic acids from chloro nitrobenzoic acids.
• Procedure 2 provides a method for the preparation of 1,3-benzothiazole-7-carboxylic acid from ethyl 3-aminobenzoate.
• the product was isolated by filtration, washed successively with acetone (5 mL) and hexanes (10 mL), and dried in a vacuum oven, thus providing the product in 95% yield as a mixture of ethyl 2-amino-1,3-benzothiazole-7-carboxylate hydrobromide and ethyl 2-amino-1,3-benzothiazole-5-carboxylate hydrobromide in a ratio of 95/5, respectively.
• This product was partitioned between saturated aqueous solution of sodium bicarbonate (25 mL) and a mixture of ethyl acetate (70 mL) and tetrahydrofuran (30 mL).
• iso-Amylnitrite 53 mmol was added to a solution of ethyl 2-amino-1,3-benzothiazole-7-carboxylate (5.40 g) in tetrahydrofuran (70 mL) and the mixture was heated at reflux for 4 h. The volatiles were removed under reduced pressure and the residue was purified by chromatography (0/100 to 5/95 methanol/dichloromethane), thus providing the ester in 71% yield.
• the mixture was maintained at room temperature for 4 h and the volatiles were removed under reduced pressure. The residue was dissolved in water (100 mL) and concentrated hydrochloric acid was added to adjust the pH of the solution to 5. The mixture was cooled to 0° C. and maintained for 30 min. The product was isolated by filtration, washed with water (10 mL), and dried in vacuum oven (70° C.) for 16 h, thus providing the acid in 91% yield.
• Literature reference Kunz et. al. U.S. Pat. No. 5,770,758.
• Procedure 3 provides a preparation of substituted benzisothiazole-3-carboxylic acids from the corresponding thiophenols.
• Procedure 4 provides a method for the preparation of isatins from anilines and the conversion of the isatins to the corresponding indazole-3-carboxylic acids.
• the amide was added to sulfuric acid (1.9 L) and the reaction mixture was heated at 60° C. for 6 h. The reaction mixture was allowed to cool to room temperature and was cautiously poured onto ice (7 kg). The precipitated solids were collected by filtration, washed with water, and dried to provide the isatin in 61% yield.
• Procedure 5 provides a method for the preparation of bromoindazoles from bromomethylanilines.
• Acetic anhydride (2.27 equiv.) was added to a cooled (0° C.) solution of bromomethylaniline (1.00 equiv.) in chloroform (1.5 mL/mmol) while maintaining the temperature below 40° C.
• the reaction mixture was allowed to warm to room temperature and was maintained for 1 h.
• Potassium acetate (0.29 eq) and isoamyl nitrite (2.15 equiv.) was added and the reaction mixture was heated at reflux for 18 h. The volatiles were removed under reduced pressure. Water (0.65 L/mol) was added to the residue and the mixture was concentrated. Concentrated hydrochloric acid (1 L/mol) was added to the residue and the mixture was heated at 50° C. for 2 h.
• the mixture was allowed to cool to room temperature and the pH was adjusted to 10 by the slow addition of a 50% aqueous sodium hydroxide solution.
• the mixture was diluted with water (0.65 L/mol) and was extracted with ethyl acetate (2 ⁇ 1.2 L/mol).
• the combined extracts were washed with brine (1 L/mol) and dried over anhydrous sodium sulfate.
• the organic solution was filtered through a plug of silica gel (ethyl acetate wash), concentrated, and the residue was triturated with heptane (1 L/mol).
• the solids were collected by filtration, rinsed with heptane, and dried in a vacuum oven, thus providing the brominated indazole in 60-80% yield.
• Procedure 6 provides a method for the preparation of indazole carboxylic acid from bromoindazole.
• Procedure 7 provides a preparation of 1H-indazole-7-carboxylic acid from 2-amino-3-methylbenzoic acid.
• Procedure 8 provides a method for the preparation of 5-nitroindazole-3-acid from ethyl indazole-3-carboxylate.
• Ethyl indazole-3-carboxylate (73.7 mmol) was dissolved in 20 mL concentrated sulfuric acid and the reaction mixture was cooled to 0° C. A mixture of concentrated sulfuric acid (12 mL) and 70% nitric acid (12 mL) was added dropwise over the course of 1 h. The mixture was stirred for an additional 1 h at 0° C. and was poured onto of crushed ice (200 g). The solid was collected by vacuum filtration, washed with several portions of water and dried in vacuo. The dried solid was suspended in 250 mL acetonitrile and the mixture was heated at reflux for 2 h.
• the mixture was allowed to cool to room temperature and the solid was collected and dried in vacuo, thus providing ethyl 5-nitroindazole-3-carboxylate in 53% yield as a colorless solid and ethyl 7-nitroindazole-3-carboxylate (5%) as a colorless solid.
• the esters were saponified using sodium hydroxide to provide the acids.
• Procedure 9 provides a method for the preparation of 6-nitroindazole-3-acid from 3-iodo-6-nitroindazole.
• a 5 mL microwave reaction vessel was charged with 3-iodo-6-nitroindazole (1 mmol), copper (I) cyanide (2 mmol) and N,N-dimethylformamide (3 mL). The vessel was sealed and subjected to microwave irradiation at 185° C. for 600 sec. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL) and the mixture was filtered through Celite. The organic layer was collected, washed with brine, dried (magnesium sulfate), and concentrated to give 122 mg of a 10 to 1 mixture of 3-cyano-6-nitroindazole and 6-nitroindazole as a yellow solid.
• 3-Iodo-6-nitroindazole was prepared from 6-nitroindazole using the method of Collot, V.; et. al. Tetrahedron 1999, 55, 6917.
• Procedure 10 provides a method for the trapping of indazole aryllithiums with ketones and the coupling with 3-aminoquinuclidine to form heterocyclic derivatives.
• tert-Butyl 6-bromoindazole-3-carboxylate was prepared from the acid by reaction with a 2-fold excess of di-tert-butyldicarbonate followed by treatment with sodium hydroxide.
• sodium hydride (60% mineral oil dispersion) (4.8 mmol) in tetrahydrofuran (40 mL) at 0° C.
• a solution of tert-butyl 6-bromoindazole-3-carboxylate 4.0 mmol
• the mixture was cooled to ⁇ 78° C.
• 6-(4-Hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid tert-butyl ester (0.86 mmol) was dissolved in trifluoroacetic acid (3 mL) and the mixture was maintained at room temperature for 16 h. The solvent was removed in vacuo and the residue was triturated with ethyl acetate to provide 6-(3,6-dihydro-2H-pyran-4-yl)-1H-indazole-3-carboxylic acid (76%).
• the acids were coupled with quinuclidine amine according to procedure A.
• 6-(4-Hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid tert-butyl ester (1.0 mmol) was taken up in trifluoroacetic acid (5 mL), triethylsilane (2 mL), and dichloromethane (3 mL) and the mixture was refluxed for 16 h. The solvent was removed in vacuo and the residue was triturated with ethyl acetate to provide 6-(tetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid (60%) as a tan solid.
• Procedure 11 provides a method for the preparation of 4-bromo-5-methoxyindazole-3-carboxylic acid from ethyl 5-methoxyindazole-3-carboxylate and describes further modifications to produce 4-substituted 5-methoxyindazole-3-acids.
• N-Bromosuccinimide (24.0 mmol) was added to a solution of ethyl 5-methoxyindazole-3-carboxylate (20.0 mmol) in acetonitrile (200 mL). The reaction mixture was maintained for 16 h and was partitioned between water (150 mL) and ethyl acetate (250 mL). The layers were separated and the organic layer was washed with brine (50 mL), dried (magnesium sulfate), and concentrated. The residue was purified by chromatography using a gradient of 90/10 to 70/30 hexanes/ethyl acetate, thus providing the 4-brominated product in 57% yield and trace quantities of the 6-brominated product.
• the 4-brominated ester was further derivatized using Suzuki (procedure G; 60-70% yields) or Negishi (procedure H; 20-40% yields) reaction conditions described below.
• the ester (3.82 mmol) was diluted with ethanol (10.0 mL) and 5 M sodium hydroxide (10.0 mL) and the reaction mixture was maintained for 4 h at ambient temperature.
• the reaction mixture was diluted with water (50 mL) and acidified to pH 1 with 6 N hydrochloric acid. The solids were collected by filtration, thus providing the acids in 80-95% yield.
• Procedure 12 provides a method for the preparation of 5-bromo-4-nitroindazole-3-carboxylic acid from ethyl 5-bromoindazole-3-carboxylate.
• Procedure 13 provides a method for the preparation of N-1-alkylated indazole-3-carboxylic acids from the corresponding indazole ester.
• the residue was purified by chromatography using a gradient of 95/5 to 80/20 hexanes/ethyl acetate to provide the 2-substituted indazole (17%) and the 1-substituted indazole (44%).
• the 1-substituted indazole (61 mg, 0.26 mmol) was suspended in ethanol (5.0 mL) and was warmed to facilitate dissolution.
• An aliquot of a 5.0 M solution of sodium hydroxide in water (2.00 mL) was added and the reaction mixture was maintained at ambient temperature for 16 h.
• the reaction mixture was diluted with water (50 mL) and was acidified with 6.0 N hydrochloric acid.
• the aqueous layer was extracted with ethyl acetate (3 ⁇ 50 mL) and the combined organic layers were washed with brine (25 mL), dried (magnesium sulfate), and concentrated, thus providing the acid in 95% yield.
• Procedure 14 provides a method for the demethylation of methoxyindazole acids and the coupling with 3-aminoquinuclidine to form hydroxy-substituted derivatives.
• Procedure 15 provides a method for the preparation of 7-fluoro-6-methoxy-1H-indazole-3-carboxylic acid and 4-fluoro-5-methoxy-1H-indazole-3-carboxylic acid from the corresponding methoxyindazole acids.
• the acid was coupled with the bicyclobase according to procedure A.
• Procedure 16 details the preparation of ethyl benzisoxazole-3-carboxylate from 2,5-dibromonitrobenzene.
• Diethyl malonate (12.6 g, 79 mmol) was added to a suspension of sodium hydride (3.16 g, 132 mmol) in dimethylsulfoxide (60 ml) over 30 min. The temperature of the reaction rose to 60° C. and the mixture clarified. 1,4-Dibromo-2-nitrobenzene (10 g, 36.0 mmol) was added and the solution was maintained for 2 h at 100° C. The reaction mixture was allowed to cool to rt and was poured into ice (300 g-400 g). The precipitated solids were isolated by filtration and dried to provide 11.0 g of the product (89%).
• the ester (11.0 g, 32.0 mmol) was diluted with a 2 N solution of sodium hydroxide (32 mL, 63 mmol) and the reaction mixture was maintained at room temperature for 16 h. The aqueous layer was extracted with dichloromethane (20 mL) and was acidified. The precipitated solids were isolated by filtration and dried to provide 7.00 g of the acid (89%).
• Procedure 17 provides a method for the preparation of 5-difluoromethoxyindazole-3-acid from 3-bromo-4-nitrophenol.
• Diethyl malonate (328 mmol) was added dropwise to a suspension of sodium hydride (328 mmol) in dimethylsulfoxide (40 mL) at 0° C. The reaction mixture was warmed to 60° C. and maintained for 0.5 h. A solution of the difluoromethyl ether (149 mmol) in dimethylsulfoxide (80 mL) was added dropwise and the reaction mixture was heated at 100° C. for 5 h. The cooled solution was poured onto ice water, and the aqueous layer was extracted with dichloromethane (3 ⁇ 100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give the crude diester in 112% yield as an oil.
• the diester (167 mmol), sodium hydroxide (500 mmol), and water (335 mL) were combined and heated at 60° C. for 1 h.
• the reaction mixture was allowed to cool to rt and the aqueous layer was washed with dichloromethane (3 ⁇ 100 mL).
• the pH of the aqueous layer was cautiously adjusted to 1 with concentrated hydrochloric acid and the reaction mixture was heated at 60° C. for 1 h.
• the suspension was cooled to 5° C. and the solids were collected by filtration and dried to provide the acid in 61% yield.
• Acetyl chloride (203 mmol) was added dropwise to ethanol (300 mL) at 0° C. After 0.5 h, the acid (101 mmol) was added and the reaction mixture was heated at reflux for 15 h. The reaction mixture was concentrated and the residue was partitioned between dichloromethane (200 mL) and saturated sodium bicarbonate (100 mL). The aqueous layer was further extracted with dichloromethane (2 ⁇ 200 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide the ester in 60% yield as a brown oil.
• the ester (60.4 mmol) was dissolved in ethanol (103 mL), diluted with water (71 mL), and was treated with ammonium chloride (243 mmol) and iron powder (301 mmol).
• the reaction mixture was heated at reflux for 10 minutes and the suspension was filtrated through Celite and the filter cake was washed with ethanol three times.
• the filtrate was concentrated, the residue was suspended in 2 N hydrochloric acid and was stirred vigorously for 0.5 h.
• the aqueous layer was washed with ethyl acetate (3 ⁇ 50 mL) and the pH adjusted to 9-10 with 5 M sodium hydroxide.
• the aqueous layer was extracted with chloroform (3 ⁇ 100 mL) and the combined organic layers were dried (magnesium sulfate).
• Acetic anhydride (392 mmol), isoamyl nitrite (291 mmol), and potassium acetate (51.0 mmol) were added to the organic layer and the suspension was heated at reflux for 16 h.
• the solution was evaporated and the residue was partitioned between saturated sodium bicarbonate (50 mL) and dichloromethane (100 mL).
• the aqueous layer was further extracted with dichloromethane (2 ⁇ 100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide the N-acetylindazole ester in 79% yield as a brown oil.
• the ester (63.8 mmol), sodium hydroxide (193 mmol), and water (65 mL) were combined and the reaction was maintained for 24 h at 60° C. After cooling to rt, the aqueous layer was washed with dichloromethane (3 ⁇ 50 mL). The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid. The precipitated solids were collected by filtration, washed with water and dichloromethane, and dried to provide the acid in 27% yield.
• Procedure 18 provides a method for the preparation of 6-difluoromethoxyindazole-3-acid from 4-nitrophenol.
• the nitro ether (149 mmol) was dissolved in ethanol (37.5 mL), diluted with water (25 mL), and was treated with ammonium chloride (84.7 mmol) and iron powder (105 mmol).
• the reaction mixture was heated at reflux for 30 minutes and the suspension was filtered through Celite. The filter cake was washed with ethanol three times and the combined filtrates were concentrated. The residue was dissolved in water and the pH adjusted to 9-10 with 5 M sodium hydroxide.
• the aqueous layer was extracted with ethyl acetate (3 ⁇ 100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to a yellow oil.
• the oil was dissolved in acetic anhydride (23.5 mmol) and the reaction mixture was maintained at rt for 16 h.
• the reaction mixture was diluted with water (50 mL) and was neutralized with solid sodium bicarbonate.
• the precipitated solids were isolated by filtration, washed with water, and dried to provide the acetamide in 62% yield as a light yellow solid.
• Acetic anhydride (19.6 mmol) was added to a solution of the acetamide (13.2 mmol) in chloroform (20 mL) and the reaction mixture was warmed to reflux. Fuming nitric acid (16.0 mmol) was added dropwise and the reaction mixture was maintained at reflux for 30 min. The cooled solution was diluted with water (20 mL) and the aqueous layer was extracted with dichloromethane (3 ⁇ 10 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to provide the nitro-amide in 83% yield.
• the amide (11.0 mmol), sodium hydroxide (43.8 mmol), and water (10 mL) were combined and the reaction mixture was maintained for 1.5 hour at 60° C. the reaction was allowed to cool to rt and the precipitated solids were isolated by filtration, and washed with water, and dried to provide the aniline in 98% yield as a light yellow solid.
• the aniline (15.7 mmol) was mixed with 40% hydrobromic acid (14.3 g) and water (10 mL) and the reaction mixture was warmed to 80-90° C. in order to completely dissolve the aniline.
• the reaction mixture was cooled to 0° C. and a solution of sodium nitrite (23.2 mmol) in water (5.3 mL) was added during a 15 min period. The solution was maintained for 40 minutes at 0-5° C. and filtered.
• Copper (I) bromide (18.8 mmol) was dissolved in 40% hydrobromic acid (21 mL) and was cooled to 0° C. The solution of the diazo salt was added slowly to the copper solution and the mixture was maintained for 30 min at 0-10° C.
• the reaction mixture was heated at 60° C. for 30 min and then at 100° C. for 10 min to ensure completion.
• the reaction mixture was allowed to cool to rt and was extracted with dichloromethane (3 ⁇ 40 mL).
• the combined organic layers were washed with 1 M sodium hydroxide, water, 1 N hydrochloric acid, and water.
• the organic layer was dried (magnesium sulfate) and concentrated to provide the nitro bromide in 76% yield as a light yellow solid.
• the diester (11.7 mmol), sodium hydroxide (35 mmol), and water (20 mL) were combined and heated at 60° C. for 1 h.
• the reaction mixture was allowed to cool to rt and the aqueous layer was washed with dichloromethane (3 ⁇ 100 mL).
• the pH of the aqueous layer was cautiously adjusted to 1 with concentrated hydrochloric acid and the reaction mixture was heated at 60° C. for 1 h.
• the suspension was cooled to 0° C. and the solids were collected by filtration and dried to provide the acid in 64% yield.
• Acetyl chloride (15.3 mmol) was added dropwise to ethanol (50 mL) at 0° C. After 30 min, the acid (7.69 mmol) was added and the reaction mixture was heated at reflux for 15 h. The reaction mixture was concentrated and the residue was partitioned between dichloromethane (20 mL) and saturated sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (2 ⁇ 20 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide the ester in 94% yield as a brown oil.
• Acetic anhydride (6.0 mL) was added to a suspension of the ester (3.64 mmol), and acetic acid (7.0 mL) at 0° C.
• Zinc dust (14.6 mmol) was added in portions over 15 min and the reaction mixture was maintained for 30 min at 0° C. and then for 1.5 h at rt. Additional zinc powder (6.15 mmol) was added and the reaction maintained for 3 h.
• the suspension was filtered through Celite and the filtrate was concentrated. The residue was partitioned between saturated sodium bicarbonate (10 mL) and ethyl acetate (20 mL). The aqueous layer was further extracted with ethyl acetate (3 ⁇ 20 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide the acetamide in 92% yield as a brown oil.
• Acetic anhydride (13.7 mmol), isoamyl nitrite (13.7 mmol), and potassium acetate (2.04 mmol) were added to a solution of the acetamide (3.92 mmol) in chloroform (20 mL) and the suspension was heated at reflux for 16 h. The solution was evaporated and the residue was partitioned between saturated sodium bicarbonate (10 mL) and dichloromethane (20 mL). The aqueous layer was further extracted with dichloromethane (2 ⁇ 20 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide the crude N-acetylindazole ester as a brown oil.
• the ester (3.36 mmol), sodium hydroxide (10 mmol) and water (5 mL) were combined and the reaction was maintained for 24 h at 60° C. After cooling to rt, the aqueous layer was washed with dichloromethane (3 ⁇ 30 mL). The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid and the precipitated solids were collected by filtration, washed with water and dichloromethane, and dried to provide the acid in 26% yield.
• Procedure 19 provides a method for the coupling between brominated benzisothiazole-3-carboxylic esters and brominated indazole-3-carboxylic esters and Grignard reagents to form alkyl- and heterocycle-substituted acids.
• the reaction was quenched with saturated ammonium chloride and was extracted with dichloromethane (3 ⁇ ). The extracts were dried over sodium sulfate and concentrated to dryness. The residue was purified by chromatography using a gradient of 100/0 to 90/10 dichloromethane/methanol to provide the alkyl- or aryl-substituted amide.
• the amide was dissolved in a mixture of methanol/tetrahydrofuran/water (90/10/20 mL) and was treated with sodium hydroxide (5.8 g). The mixture was heated at reflux for 12 h, cooled to rt, filtered, and was acidified to pH ⁇ 2 by the slow addition of conc. hydrochloric acid. The aqueous layer was extracted with ethyl acetate (2 ⁇ ) and was dried over sodium sulfate. Concentration of the extracts gave the acid in 38% yield. The acid was coupled to the bicyclobases according to procedure A.
• Procedure 20 provides a method for the preparation of alkoxy indazole acids from the corresponding benzyloxy indazole esters using alkylation conditions.
• the reaction was partitioned between water (50 mL) and ethyl acetate (50 mL) and the organic layer was washed with brine (25 mL), dried (magnesium sulfate), and concentrated. The residue was purified by chromatography (95/5 to 85/15 hexanes/ethyl acetate to provide the protected indazole in 89% yield.
• the residue was purified by chromatography (100/0 to 85/15 hexanes/ethyl acetate) to yield the purified ethyl ester.
• the ester was dissolved in ethanol (10 mL) and 5 N sodium hydroxide (3 mL) was added. The mixture was allowed to stand overnight and was diluted with water (20 mL) and acidified to pH 1 with 3 N hydrochloric acid. The solid was collected by vacuum filtration to give the acid in 72% yield as a white solid.
• Procedure 21 provides a method for the preparation of alkoxy indazole acids from the corresponding benzyloxy indazole esters using Mitsunobu conditions.
• Procedure 22 provides a method for the preparation of 1-(3-thienyl)-1H-indazole-3-carboxylic acid from the corresponding indazole ester.
• Procedure 23 provides a method for the preparation of 1,8-dihydropyrrolo[3,2-g]indazole-3-carboxylic acid from ethyl 6-bromo-7-nitro-1H-indazole-3-carboxylate.
• the reaction was partitioned between water (50 mL) and ethyl acetate (50 mL), filtered through Celite and the organic layer was washed with brine (25 mL), dried (magnesium sulfate), and concentrated. The residue was purified by chromatography (80/20 to 60/40 hexanes/ethyl acetate) to yield the dioxolane product in 46% yield.
• Ethyl 1,8-dihydropyrrolo[3,2-g]indazole-3-carboxylate (0.266 mmol) was dissolved in ethanol (2 mL) and 5.0 M of sodium hydroxide (1.00 mL) and the reaction was maintained for 16 h.
• the reaction mixture was neutralized with 3 N hydrochloric acid and was partitioned between water (30 mL) and ethyl acetate (30 mL). The layers were separated and the organic layer was washed with brine (25 mL), dried (magnesium sulfate), and concentrated in vacuo to provide the acid in 41% yield. The acid was used without further purification.
• Procedure 24 provides a method for the preparation of alkoxypyrrolidine substituted indazole-3-carboxylic acids from the corresponding nitro-1H-indazole-3-carboxylates.
• the reaction was shaken under an atmosphere of hydrogen for 4 h and the reaction mixture was filtered through Celite and concentrated. The residue was purified by chromatography (70/30 to 50/50 hexanes/ethyl acetate) to yield the aniline in 60% yield as a 2/1 mixture of 1- and 2-SEM regioisomers.
• the reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL) and the organic layer was washed with brine (25 mL), dried (magnesium sulfate), and concentrated. The residue was purified by chromatography (90/10 to 80/20 hexanes/ethyl acetate) to yield the alkoxypyrrolidine in 42% yield.
• the ester (0.172 mmol) was dissolved in ethanol (5.0 mL) by warming slightly. A 5.0 M of sodium hydroxide (2.00 mL) was added and the reaction mixture was maintained overnight. The reaction mixture was diluted with water (50 mL), neutralized to pH 6-7 with 3.0 N hydrochloric acid, and was extracted with ethyl acetate (2 ⁇ 25 mL). The organic layer was washed with brine (25 mL), dried (magnesium sulfate), and concentrated to provide the acid in 89% yield. The acid was used with no further purification.
• Procedure 25 provides a method for the preparation of aminomethyl substituted indazole-3-carboxylic acids from the corresponding bromides.
• the reaction mixture was allowed to cool to rt, diluted with ethyl acetate, washed with water, sodium bicarbonate, and brine, dried (sodium sulfate) and concentrated.
• the residue was dissolved in 1/1 hexanes/ethyl acetate ( ⁇ 300 mL) and filtered through of silica gel (approx. 40 g).
• the silica was washed with additional 1/1 hexanes/ethyl acetate (500 mL) and the combined eluant was concentrated.
• the residue was dissolved in methanol (100 mL) and tetrahydrofuran (100 mL) and was treated with 2.0 M sodium hydroxide (100 mL).
• the reaction mixture was maintained for 2 h at rt and was partitioned between water (200 mL) and ethyl acetate (200 mL). The organic layer was washed with brine (50 mL), dried (magnesium sulfate), and concentrated. The residue was triturated with hexanes to provide the ester in 80% yield.
• tert-Butyl 5-[(dimethylamino)methyl]-1H-indazole-3-carboxylate (1.74 mmol) was dissolved in trifluoroacetic acid (3.00 mL) and the reaction mixture was maintained for 16 h. The reaction mixture was concentrated and was loaded onto a SCX column (10 g) and flushed with 5 volumes of methanol. The purified product was then eluted using 2.0 M ammonia in methanol to provide the acid in 90% yield.
• Procedure 26 provides a method for the preparation of 4-methoxyindazole acid from 4-methoxyaniline.
• a solution of sodium nitrite (1.48 mol) in water (250 mL) was added to a cold (0-5° C.) solution of the nitroaniline (1.08 mol) in hydrobromic acid (4.87 mol) (prepared by heating the reaction mixture at 90° C. for 2 h).
• the reaction mixture was maintained for 40 min and was filtered.
• the filtrate was added dropwise to a cold (0-5° C.) solution of copper (I) bromide (1.81 mol) in hydrobromic acid (640 mL) and the reaction mixture was maintained for 30 min.
• the reaction mixture was warmed to 60° C. and was maintained for 30 min.
• the reaction mixture was warmed to reflux and was maintained for 1 h.
• the reaction mixture was diluted with water (2 L) and was extracted with dichloromethane (3 ⁇ 1 L). The combined organic layers were washed with 10% sodium hydroxide (1.0 L), water (2.0 L), 10% hydrochloric acid (1.6 L) and water (2.0 L), dried (magnesium sulfate) and concentrated. The residue was recrystallized from ethanol to provide the bromide in 50% yield as a yellow solid.
• the aqueous layer was decanted and the residual red oil, which solidifies upon standing, was purified by chromatography (6/6/1 petroleum ether/dichloromethane/ethyl acetate) to provide the ⁇ -oxime amide in 29% yield as a light yellow solid.
• the ⁇ -oxime amide (58.6 mmol) was added in one portion to warm (40° C.) 90% sulfuric acid (16 mL) and the reaction mixture was heated at 60° C. for 30 min. The reaction mixture was allowed to cool to rt and was poured into ice water. The precipitated orange solids were collected by filtration and dried. The crude product was purified by chromatography (15/1 petroleum ether/ethyl acetate) to provide the isatin in 57% yield as a yellow solid.
• the isatin (20.7 mmol) was mixed with 1 M sodium hydroxide (23 mL) and the reaction mixture was heated to 30-40° C. for 30 min.
• the reaction mixture was cooled to 0° C. and treated with a solution of sodium nitrite (20.7 mmol) in water (5.1 mL) and was maintained for 20 min. That solution was added dropwise to a cold (0-5° C.) solution of concentrated sulfuric acid (2.24 mL) in water (43.3 mL) and the reaction mixture was maintained for 0.5 h.
• a solution of tin (II) chloride (50.5 mmol) in concentrated hydrochloric acid (19.6 mL) was added dropwise and the reaction mixture was maintained at 0-5° C. for 1 h.
• the precipitated solids were isolated by filtration and dried to provide the indazole acid as a yellow solid (100% by mass).
• Acetylchloride (18 mL) was added to methanol (180 mL) at 0° C. and the reaction mixture maintained for 1 h.
• the indazole acid (21.8 mmol) was added and the reaction mixture was heated at reflux for 3 h.
• the solution was concentrated to dryness and the residue was suspended in water and the pH adjusted to 7 with saturated sodium hydrogen carbonate.
• the mixture was extracted with ethyl acetate (3 ⁇ 100 mL), and the combined organic layers were dried (magnesium sulfate) and concentrated.
• the crude product was purified by chromatography (2/1 petroleum ether/ethyl acetate) to provide the indazole ester in 5% yield (two steps) as a yellow solid.
• Procedure 27 provides a method for the preparation of benzyloxy-substituted indazole-3-carboxylic acids and esters from the corresponding bromides.
• Acetic anhydride (34 mL) and zinc dust (4.59 mmol) were added to a solution of 4-methoxynitrobenzene (230 mmol) in glacial acetic acid (34 mL) and the reaction mixture was heated at reflux for 0.5 h.
• the reaction mixture was poured into water (340 mL) and the pH of the solution was adjusted to 8 with 10% sodium hydroxide.
• the precipitated solids were isolated by filtration, washed with water (100 mL), and dried to provide the acetamide in 88% yield.
• nitroacetamide 180 mmol was added to 4 M sodium hydroxide (180 mL) and the reaction mixture was maintained for 2 h at 60° C.
• the precipitated solids were isolated by filtration, washed with water, and dried to provide the nitroaniline in 70% yield as a red solid.
• the reaction mixture was partitioned between water (2.0 L) and dichloromethane (600 mL) and the aqueous layer was further extracted with dichloromethane (300 mL).
• the combined organic layers were washed with 10% sodium hydroxide (200 mL), water (600 mL), 10% hydrochloric acid (300 mL), and water (600 mL), dried (magnesium sulfate) and concentrated to provide the nitrobromide in 83% yield as a yellow oil.
• Benzyl bromide (131 mmol) and potassium carbonate (130 mmol) were added to a solution of the nitrophenol (87.0 mmol) in 2/1 acetonitrile/acetone (840 mL).
• the reaction mixture was heated at reflux for 17 h and was concentrated to dryness.
• the residue was suspended in ethyl acetate (756 mL), filtered, and the organic layer was washed with water (567 mL), 1 M hydrochloric acid (2 ⁇ 567 mL), and brine (567 mL).
• the organic layer was dried (magnesium sulfate) and concentrated to the benzyl ether in 78% yield.
• Diethyl malonate (890 mmol) was added drop wise over 1 h to a suspension of sodium hydride (520 mmol) in dimethylsulfoxide (100 mL) at 0° C.
• the benzyl ether (44.0 mmol) was added and the reaction mixture was heated at 100° C. for 5 h.
• the reaction mixture was poured into ice water and was extracted with ethyl acetate (3 ⁇ 70 mL).
• the combined organic layers were dried (magnesium sulfate) and concentrated to provide the diethylmalonate addition product.
• the diethylmalonate addition product was diluted with a 4 M solution of sodium hydroxide (100 mL) and the reaction mixture was heated at 60° C. for 6 h.
• the solution was extracted with dichloromethane (3 ⁇ 50 mL) and the aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid.
• the reaction mixture was heated at 60° C. for 1 h, allowed to cool to rt, and was extracted with ethyl acetate (3 ⁇ 50 mL).
• the combined organic layers were dried (magnesium sulfate) and concentrated to provide the phenylacetic acid in 78% yield as a solid.
• the phenylacetic acid (350 mmol) was added to a freshly prepared solution of ethanolic hydrochloric acid [acetyl chloride (5 mL) was added to ethanol (100 mL)] and the reaction mixture was heated at reflux for 20 h. The reaction mixture was concentrated to dryness and the residue was partitioned between saturated sodium bicarbonate (200 mL) and ethyl acetate (150 mL). The aqueous layer was extracted with ethyl acetate (2 ⁇ 50 mL) and the combined organic layers were dried (magnesium sulfate), filtered and concentrated to provide the ester in 77% yield.
• the nitro ester (27.0 mmol) was dissolved in acetic acid (60 mL) and acetic anhydride (44 mL) and was cooled to 0° C.
• Zinc dust 153 mmol was added and the reaction mixture was allowed to warm to rt and was maintained for 2 h. Additional quantities of zinc dust (2 ⁇ 45.9 mmol) were added during a 3 h course of time.
• the reaction mixture was filtered and the filter cake was washed with ethanol (100 mL).
• the combined filtrates were concentrated and the residue was partitioned between saturated sodium bicarbonate and ethyl acetate (50 mL).
• the solution was extracted with ethyl acetate (2 ⁇ 50 mL) and the combined organic layers were dried (magnesium sulfate), filtered and concentrated to provide the acetamide in 82% yield.
• the acetylated indazole ester (15.0 mmol) was suspended in 2 M sodium hydroxide (35 mL) and the reaction mixture was heated at 60° C. for 24 h. The pH of the solution was adjusted to 1-2 with concentrated hydrochloric acid and the solids were collected by filtration and dried to provide 6-benzyloxy-1H-indazole-3-carboxylic acid in 28% yield as a yellow solid.
• 6-Benzyloxy-1H-indazole-3-carboxylic acid (1.85 mmol) was added to a freshly prepared solution of ethanolic hydrochloric acid [prepared from ethanol (20 mL) and acetyl chloride (5 mL)] and the reaction mixture was heated at reflux for 25 h and was concentrated. The residue was partitioned between saturated sodium bicarbonate (20 mL) and ethyl acetate (20 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 ⁇ 20 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated.
• ethanolic hydrochloric acid prepared from ethanol (20 mL) and acetyl chloride (5 mL)
• the ester can be obtained from the acetylated indazole ester by maintaining the acetylated material in 2 M ammonia in methanol for 30 min.
• Procedure 28 provides a method for the preparation of N-alkylated 3-aminoquinuclidines from 3-aminoquinuclidine.
• the filtrate was concentrated and the residue was then diluted with freshly prepared methanolic hydrogen chloride (generated by the dropwise addition of 3 mL of acetyl chloride into 30 mL of methanol) and maintained at rt for 15 min.
• the residue obtained by the removal of the volatiles was recrystallized (2-propanol/methanol) to provide the secondary amine in 41% yield as a colorless solid.
• Procedure 29 provides a method for the preparation of 1-(1-azabicyclo[2.2.2]oct-3-yl)methanamine dihydrochloride from quinuclidinone.
• the aqueous layer was further extracted with 9/1 dichloromethane/methanol (5 ⁇ 100 mL) and the combined organic layers were concentrated.
• the residue was purified by chromatography [90/10/1 dichloromethane/methanol/ammonium hydroxide or 1/1 to 0/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] or by preparative HPLC, thus providing the product in 30%-70% yield.
• Procedure B provides a method for the coupling between 3-aminoquinuclidine and benzisothiazole carboxylic acids to form carboxamide derivatives.
• the mixture was partitioned between saturated aqueous potassium carbonate solution and a 95/5 mixture of dichloromethane/methanol.
• the aqueous layer was extracted with 95/5 dichloromethane/methanol (2 ⁇ ), and the combined organic layers were washed with brine and dried over sodium sulfate.
• the crude product was purified by chromatography (90/10/1 dichloromethane/methanol/ammonium hydroxide) or by preparative HPLC, thus providing the amide in 75% yield as a colorless solid.
• Procedure C provides a method for the coupling between 3-aminoquinuclidine and carboxylic acids to form carboxamide derivatives.
• Procedure D provides a method for the coupling between 3-aminoquinuclidine and carboxylic acids to form carboxamide derivatives.
• the coupling reaction and purification was performed according to procedures A and C (indazoles, benzthiazoles) or according to procedure B (benzisothiazoles).
• the free base was dissolved in methanol (3.5 mL/mmol starting acid) and treated with 1N hydrochloric acid in ether (3.5 mL/mmol starting acid).
• the resulting suspension was diluted with ether (7 mL/mmol starting acid) and was maintained at room temperature for 2 h.
• the solids were collected by filtration, rinsed with ether, and dried, thus providing the hydrochloride salt in 40-60% yield.
• Procedure E provides a method for the formation of carboxamide derivatives from methyl 3-quinuclidinecarboxylic acid ester.
• Procedure F provides a method for the reduction of the carboxamide to form secondary amine derivatives.
• Procedure G provides a method for the coupling between brominated and iodinated aminoquinuclidinecarboxamides and boronic acids to form aryl-substituted derivatives.
• Procedure H provides a method for the coupling between brominated 3-aminoquinuclidinecarboxamides and Grignard reagents to form alkyl-substituted derivatives.
• a 5 mL microwave reaction vessel was charged with bis(triphenylphosphine)palladium (II) chloride (0.030 mmol, 0.1 eq) and the bromide (0.30 mmol).
• the vessel was evacuated and back-filled with argon gas.
• solution of the Grignard 1.2 mmol, 4 eq
• zinc chloride 1.2 mmol, 4 eq
• the suspension was maintained for 30 min and the entire contents were transferred to the reaction vessel via cannula.
• the vessel was sealed and subjected to microwave irradiation at 100° C. for 600 sec with a pre-stir time of 60 s.
• the reaction was quenched with acetic acid (0.5 mL), diluted with methanol, and was transferred to a SCX column.
• the column was washed with methanol (50 mL) and the product was eluted with 2 M ammonia in methanol (50 mL) and concentrated.
• the residue was purified by chromatography [90/10/1 dichloromethane/methanol/ammonium hydroxide or 1/1 to 0/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] or by preparative HPLC, thus providing the product in 20-50% yield.
• the Grignard reagent of thiazole is commercially available.
• the aryllithium and the corresponding arylzinc reagent can be generated according to the procedure outlined by Reeder, M. R.; et. al. Org. Proc. Res. Devel. 2003, 7, 696.
• the zinc reagents of oxazole, 1-methylimidazole, and related reagents were prepared according to this procedure.
• Procedure I provides a method for the coupling between brominated 3-aminoquinuclidinecarboxamides and acetylenes to form alkynyl-substituted derivatives.
• a 5 mL microwave reaction vessel was charged with bis(triphenylphosphine)palladium (II) chloride (0.0597 mmol, 0.1 eq), copper (I) iodide (0.0719 mmol, 0.12 eq.), triphenylphosphine (0.124 mmol, 0.2 eq.), and the bromide (0.578 mmol).
• the vessel was evacuated and back-filled with argon gas.
• the alkyne (0.71 mmol, 1.2 eq), diethylamine (3.5 mL), and N,N-dimethylformamide (1.5 mL) were added and the vessel was sealed and subjected to microwave irradiation at 120° C. for 1500 sec.
• the reaction was reduced under vacuum to ⁇ 1.5 mL and was transferred to a SCX column.
• the column was washed with methanol (50 mL) and the product was eluted with 2 M ammonia in methanol (50 mL) and concentrated.
• the residue was purified by chromatography [1/1 to 0/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] to provide the silylacetylene in 90-95% yield.
• the silane was dissolved in tetrahydrofuran (2.5 mL) and was treated with tetrabutylammonium fluoride (0.6 mL of a 1 M solution in tetrahydrofuran).
• the reaction mixture was maintained for 11 h and was transferred to a SCX column.
• the column was washed with methanol (50 mL) and the product was eluted with 2 M ammonia in methanol (50 mL) and concentrated.
• the residue was purified by preparative HPLC, thus providing the product in 40-60% yield.

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